CN105980361B - 用于治疗心血管疾病的5-苄基异喹啉衍生物 - Google Patents

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Publication number

CN105980361B

CN105980361B CN201580008635.9A CN201580008635A CN105980361B CN 105980361 B CN105980361 B CN 105980361B CN 201580008635 A CN201580008635 A CN 201580008635A CN 105980361 B CN105980361 B CN 105980361B

Authority

CN

China

Prior art keywords

nmr

dmso

isoquinolin

base

ethyl

Prior art date

2014-02-21

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 208000024172 Cardiovascular disease Diseases 0.000 title description 3
• 150000005520 5-benzylisoquinolines Chemical class 0.000 title description 2
• 201000010099 disease Diseases 0.000 claims abstract description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
• 239000011435 rock Substances 0.000 claims abstract description 10
• 230000026731 phosphorylation Effects 0.000 claims abstract description 7
• 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 7
• 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 claims abstract description 6
• 108010067385 Myosin Light Chains Proteins 0.000 claims abstract description 6
• 102000016349 Myosin Light Chains Human genes 0.000 claims abstract description 6
• 101150111584 RHOA gene Proteins 0.000 claims abstract description 6
• 230000004913 activation Effects 0.000 claims abstract description 6
• 238000006467 substitution reaction Methods 0.000 claims abstract description 3
• 239000002585 base Substances 0.000 claims description 289
• AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 185
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 148
• 238000005859 coupling reaction Methods 0.000 claims description 109
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 107
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 99
• 150000001875 compounds Chemical class 0.000 claims description 98
• 230000003287 optical effect Effects 0.000 claims description 88
• -1 Cyclohexyl Chemical group 0.000 claims description 79
• 239000002253 acid Substances 0.000 claims description 74
• 150000003839 salts Chemical class 0.000 claims description 73
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 53
• 238000000034 method Methods 0.000 claims description 51
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 50
• 150000002576 ketones Chemical class 0.000 claims description 47
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
• 238000006722 reduction reaction Methods 0.000 claims description 31
• 238000002360 preparation method Methods 0.000 claims description 26
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 25
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
• 229910052799 carbon Inorganic materials 0.000 claims description 21
• 239000001257 hydrogen Substances 0.000 claims description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• GBABOEBIUROCDV-UHFFFAOYSA-N 1-fluoro-2,3-dihydro-1h-indene Chemical class C1=CC=C2C(F)CCC2=C1 GBABOEBIUROCDV-UHFFFAOYSA-N 0.000 claims description 16
• VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
• 125000005843 halogen group Chemical group 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 125000000623 heterocyclic group Chemical group 0.000 claims description 11
• LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 claims description 10
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 10
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
• 210000002216 heart Anatomy 0.000 claims description 10
• 239000003054 catalyst Substances 0.000 claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 208000010412 Glaucoma Diseases 0.000 claims description 6
• 206010020772 Hypertension Diseases 0.000 claims description 6
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
• 239000003513 alkali Substances 0.000 claims description 6
• HFXKQSZZZPGLKQ-UHFFFAOYSA-N cyclopentamine Chemical compound CNC(C)CC1CCCC1 HFXKQSZZZPGLKQ-UHFFFAOYSA-N 0.000 claims description 5
• 229960003263 cyclopentamine Drugs 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 150000002430 hydrocarbons Chemical group 0.000 claims description 5
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
• 239000010948 rhodium Substances 0.000 claims description 5
• 239000012279 sodium borohydride Substances 0.000 claims description 5
• 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
• 206010016654 Fibrosis Diseases 0.000 claims description 4
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
• 208000037849 arterial hypertension Diseases 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims description 4
• 208000010125 myocardial infarction Diseases 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 4
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
• 201000001320 Atherosclerosis Diseases 0.000 claims description 3
• 208000010228 Erectile Dysfunction Diseases 0.000 claims description 3
• 206010019280 Heart failures Diseases 0.000 claims description 3
• XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims description 3
• 206010029164 Nephrotic syndrome Diseases 0.000 claims description 3
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 3
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• 125000004429 atom Chemical group 0.000 claims description 3
• 230000008859 change Effects 0.000 claims description 3
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• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 206010012601 diabetes mellitus Diseases 0.000 claims description 3
• 229940079593 drug Drugs 0.000 claims description 3
• 230000004761 fibrosis Effects 0.000 claims description 3
• BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 3
• 201000001881 impotence Diseases 0.000 claims description 3
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• 210000003734 kidney Anatomy 0.000 claims description 3
• 208000019423 liver disease Diseases 0.000 claims description 3
• 208000009928 nephrosis Diseases 0.000 claims description 3
• 231100001027 nephrosis Toxicity 0.000 claims description 3
• 239000003960 organic solvent Substances 0.000 claims description 3
• 229910052763 palladium Inorganic materials 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
• 150000003235 pyrrolidines Chemical class 0.000 claims description 3
• 208000037803 restenosis Diseases 0.000 claims description 3
• 229910052703 rhodium Inorganic materials 0.000 claims description 3
• MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
• YDBHSDRXUCPTQQ-UHFFFAOYSA-N 1-methylcyclohexan-1-amine Chemical group CC1(N)CCCCC1 YDBHSDRXUCPTQQ-UHFFFAOYSA-N 0.000 claims description 2
• 201000006474 Brain Ischemia Diseases 0.000 claims description 2
• 206010008120 Cerebral ischaemia Diseases 0.000 claims description 2
• PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 2
• LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
• 206010022489 Insulin Resistance Diseases 0.000 claims description 2
• 201000009594 Systemic Scleroderma Diseases 0.000 claims description 2
• 206010042953 Systemic sclerosis Diseases 0.000 claims description 2
• 208000007536 Thrombosis Diseases 0.000 claims description 2
• 125000000217 alkyl group Chemical group 0.000 claims description 2
• 206010008118 cerebral infarction Diseases 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 206010061989 glomerulosclerosis Diseases 0.000 claims description 2
• 201000001421 hyperglycemia Diseases 0.000 claims description 2
• 210000004072 lung Anatomy 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
• 231100000252 nontoxic Toxicity 0.000 claims description 2
• 230000003000 nontoxic effect Effects 0.000 claims description 2
• 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
• 230000005855 radiation Effects 0.000 claims description 2
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 2
• 125000004432 carbon atom Chemical group C* 0.000 claims 7
• 230000002194 synthesizing effect Effects 0.000 claims 3
• QFRGLNMYAGDIGJ-UHFFFAOYSA-N 5-(2,6-difluoro-4-piperidin-2-ylbenzoyl)-2H-isoquinolin-1-one Chemical compound FC1=C(C(=O)C2=C3C=CNC(C3=CC=C2)=O)C(=CC(=C1)C1NCCCC1)F QFRGLNMYAGDIGJ-UHFFFAOYSA-N 0.000 claims 1
• LGDWLHZEGZDFKO-UHFFFAOYSA-N 5-[4-(1-amino-2-cyclohexylethyl)-2,6-difluorobenzoyl]-2H-isoquinolin-1-one Chemical compound NC(CC1CCCCC1)C1=CC(=C(C(=O)C2=C3C=CNC(C3=CC=C2)=O)C(=C1)F)F LGDWLHZEGZDFKO-UHFFFAOYSA-N 0.000 claims 1
• 208000004998 Abdominal Pain Diseases 0.000 claims 1
• 208000002881 Colic Diseases 0.000 claims 1
• 208000002193 Pain Diseases 0.000 claims 1
• 230000008901 benefit Effects 0.000 claims 1
• 230000000747 cardiac effect Effects 0.000 claims 1
• 239000000835 fiber Substances 0.000 claims 1
• 206010023365 keratopathy Diseases 0.000 claims 1
• 230000015572 biosynthetic process Effects 0.000 abstract description 42
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• 230000002265 prevention Effects 0.000 abstract description 2
• 239000000543 intermediate Substances 0.000 description 1099
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 690
• 238000005160 1H NMR spectroscopy Methods 0.000 description 403
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 258
• 239000000243 solution Substances 0.000 description 172
• 239000000203 mixture Substances 0.000 description 167
• CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 146
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 118
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• HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 106
• 230000008878 coupling Effects 0.000 description 101
• 238000010168 coupling process Methods 0.000 description 101
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 82
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• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 80
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 75
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
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• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 37
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